NAD+ in humans: precursors, infusions and what the trials measure

A coenzyme that runs down with age

NAD+ is the electron carrier of mitochondrial respiration and the substrate of sirtuins and PARPs, the DNA-repair enzymes. In a study of 49 human skin samples from people aged 0 to 77, investigators found a strong negative correlation between NAD+ and age in both men (r = −0.706) and women (r = −0.537). In men, PARP activity rose with age and correlated inversely with tissue NAD+¹.

The second proposed mechanism is the enzyme CD38. In mice, its expression and activity increased with aging, and CD38 was required for the age-related NAD+ decline and mitochondrial dysfunction. The same work identified CD38 as the main enzyme degrading the precursor NMN in vivo². That finding links to another strategy under study: inhibiting enzymes that consume nicotinamide, such as NNMT, the subject of our article on 5-amino-1MQ.

Oral precursors: NAD+ does go up

The best-studied route in humans is not NAD+ itself but its precursors: nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). In a 2 × 6-week randomized, double-blind, crossover trial in healthy middle-aged and older adults, NR was well tolerated and effectively stimulated NAD+ metabolism; the authors suggested studying its possible effect on blood pressure and arterial stiffness³. In 12 older men, 1 g of NR daily for 21 days raised the skeletal-muscle NAD+ metabolome and lowered circulating inflammatory cytokines, without changing mitochondrial bioenergetics⁴.

The NADPARK trial took the question to the brain. Thirty newly diagnosed, treatment-naive patients with Parkinson's disease received 1,000 mg of NR or placebo for 30 days. NR was well tolerated and was associated with a significant but variable increase in cerebral NAD+ measured by phosphorus-31 magnetic resonance spectroscopy. In those whose brain NAD+ rose, cerebral metabolism changed and this was associated with mild clinical improvement⁶.

From biomarkers to clinical signals

Some trials measure more than metabolites. In a 10-week randomized, placebo-controlled, double-blind trial in postmenopausal women with prediabetes and overweight or obesity, NMN increased insulin-stimulated glucose disposal, measured by hyperinsulinemic-euglycemic clamp, and muscle insulin signaling; placebo produced no change⁵. In the NICE trial of 90 people with peripheral artery disease, 6 months of NR improved 6-minute walk versus placebo (+7.0 m vs −10.6 m; difference +17.6 m, 90% CI +1.8 to +∞); resveratrol added no benefit⁷.

Meta-analyses put those signals in proportion. Across 10 trials with 349 participants with elevated blood pressure, NMN was associated with a modest reduction in diastolic pressure (−2.15 mmHg), with no significant change in systolic pressure except in the subgroup aged 60 and over (−3.94 mmHg)¹². Across 15 trials (10 with safety data), oral NMN did not increase adverse events or transaminases, but it did not change weight, fasting glucose, HbA1c or lipids either¹³. In trials of adults with a mean age over 60, the evidence did not support NMN or NR for preserving muscle mass or function¹¹.

Intravenous NAD+: what is known about its pharmacokinetics

NAD+ given directly has far less literature. The reference study is a pilot in 11 healthy men aged 30 to 55: 8 received 750 mg of intravenous NAD+ over 6 hours and 3 received saline; according to the authors, the dose reflected a common clinic regimen. Surprisingly, plasma NAD+ and its metabolites did not change until after 2 hours: at that infusion rate, NAD+ was rapidly and completely removed from plasma. The metabolite profile was consistent with NAD+ glycohydrolase and pyrophosphatase activity, and at 6 hours urinary excretion of NAD+ and methylnicotinamide increased. No adverse events were observed during the infusion⁸.

One of the few randomized trials of intravenous NAD+ is in cardiology, not longevity. In a single-center trial of 180 adults with heart failure due to ischemic cardiomyopathy (LVEF ≤ 45%), 10 mg/day of intravenous NAD+ for 7 days, on top of standard therapy, was associated with higher LVEF at one month (45.44% vs 42.44%; p = 0.024). Major cardiovascular events at 6 months were less frequent (14.6% vs 24.7%), but the difference was not significant (p = 0.089)⁹.

Where the evidence ends

Raising a biomarker is not the same as a clinical benefit. A 2026 systematic review examined 33 human intervention studies (28 randomized): oral precursors showed consistent biochemical effect and good tolerability, but functional, metabolic and vascular effects were "heterogeneous and often null or endpoint-specific". It found no outcome trial of intravenous or intramuscular NAD+ for anti-aging or wellness¹⁰. Our longevity article places NAD+ alongside epitalon, MOTS-c and SS-31.

On infusions, a 2026 narrative review describes sparse human evidence, mostly small uncontrolled studies and isolated case reports. Reported adverse effects include nausea, cramping, flushing and chest discomfort, and long-term safety data are lacking. The same review notes that recent large-scale human data indicate whole-blood NAD+ does not decline with healthy aging per se¹⁴, a nuance next to the tissue findings¹.